We are proposing to conduct a study of the effectiveness and safety of nortriptyline treatment of depression in two samples of elderly nursing home residents with symptoms of major depression, those who are cognitively intact and those with coexisting dementia. We propose to enter 60-65 patients in each group and estimate that the final sample will include 50 treatment completers in each group. Although all subjects will have symptoms of major depression, the sample will vary considerably in its clinical features. Patients with bipolar disease and those with psychotic depressions will be excluded but the admission criteria will allow investigation of patients of varying severity and varying duration of the current episode, the presence or absence of features of melancholia, and early versus late onset, as well as differences in comorbid medical disorders and dementia. The treatment protocol will consist of two phases. In Phase One, patients will be treated under single blind conditions with a placebo for a period of one week and then they will be randomly assigned to ten weeks of treatment with one of two dose regimens of nortriptyline chosen to ensure a wide distribution of final steady state plasma levels; one regimen will be limited to "low" doses, up to 10 mg/day, while the other will allow more "usual" doses, up to 60 mg/day. In Phase Two, non-responders from Phase One will be treated for another eight week period with doses of nortriptyline adjusted to achieve plasma levels in the range 80-120 ng/ml, while patients with plasma levels in this range will be continued. Patients will be monitored during treatment with assessment of plasma levels of nortriptyline (total and free), active metabolites, and binding proteins, as well as measures of symptoms, affective, cognitive, functional, nutritional, and medical status. The data obtained from these studies will be used to provide clinicians with practical guidelines for the treatment of depression in the frail elderly, both in the nursing home and the community, to use plasma level-response relationships as a probe for identifying treatment- relevant types of depression, and to further develop fixed dose treatment with nortriptyline as a standard control for use in subsequent treatment studies.